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Effector mechanisms of non-canonical inflammasome activation

Rühl, Sebastian. Effector mechanisms of non-canonical inflammasome activation. 2018, Doctoral Thesis, University of Basel, Faculty of Science.

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Official URL: http://edoc.unibas.ch/diss/DissB_12628

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Abstract

Our body constantly faces all kinds immunological challenges, ranging from sterile wounds
to non-pathogenic and sometimes pathogenic microorganisms. The innate immune system
represents the first line of defense against these challenges. It is capable of detecting invading
microorganisms and tissue damage by conserved, germline-encoded pattern recognition
receptors (PRRs) and launches a first counterstrike through mechanisms including
phagocytosis, reactive oxygen species (ROS) or anti-microbial peptides. Concomitant
production and secretion of cytokines alerts the adaptive immune system and initializes are
very potent, highly specific and sustained immune response governed by the activation and
expansion of T- and B-cells.
Inflammasomes are one important class of cytosolic PRRs as they recognize a large variety
of pathogens. Engagement of inflammasome pathways leads to death of the infected host cell
by pyroptosis and secretion of pro-inflammatory cytokines like IL-1b and IL-18. The recently
discovered non-canonical inflammasome pathway is triggered by intracellular bacterial
lipopolysaccharide (LPS), which binds to caspase-11 to activate it. Active caspase-11 triggers
pyroptosis and activates a canonical Nlrp3 inflammasome to promote caspase-1 activation
and IL-1 secretion.
The molecular details of pyroptosis execution and the signaling events downstream of
caspase-11 have not been thoroughly characterized, which is why this was the main interest
underlying my PhD work. I investigated the connection between caspase-11 activation and
cytokine release triggered by the canonical NLRP3 inflammasome. I could show that
caspase-11 stimulates NLRP3 activation by promoting potassium efflux, a well characterized
trigger for the NLRP3 inflammasome, in a cell autonomous manner. Subsequently I got
interested in the molecular mechanisms underlying pyroptosis induction by Gasdermin-D.
We could characterize pore formation by the Gasdermin-D N-terminal fragment as the final
step of pyroptosis. Finally, I investigated if cells are capable of preventing or delaying
pyroptosis downstream of caspase-11/gasdermin-D. I found that removal of Gasdermin-D
pores by ESCRT-III mediated membrane repair represents one mechanism by which cells
prevent Gasdermin-D dependent cell death. Overall my results revealed connections between
innate immunity signaling pathways, uncovered a novel form of cellular pore forming toxins
and demonstrated an unexpected regulation of pyroptosis by cellular survival pathways.
Advisors:Hiller Odermatt, Sebastian and Broz, Petr and Pieters, Jean
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Former Organization Units Biozentrum > Infection Biology (Broz)
05 Faculty of Science > Departement Biozentrum > Infection Biology > Biochemistry (Pieters)
05 Faculty of Science > Departement Biozentrum > Structural Biology & Biophysics > Structural Biology (Hiller)
UniBasel Contributors:Rühl, Sebastian and Hiller Odermatt, Sebastian and Broz, Petr and Pieters, Jean
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:12628
Thesis status:Complete
Bibsysno:Link to catalogue
Number of Pages:1 Online-Ressource (137 Seiten)
Language:English
Identification Number:
Last Modified:08 Jun 2018 04:30
Deposited On:07 Jun 2018 10:51

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